The global, regional and national burden of stomach cancer and its attributable risk factors from 1990 to 2019

We aimed to estimate the incidence, mortality, and disability-adjusted life-years (DALYs) of stomach cancer at the global, regional, and national levels. Stomach cancer resulted in 1.3 million (1.2–1.4 million) incident cases, 9.5 hundred thousand (8.7–10.4 hundred thousand) deaths, and 22.2 million (20.3–24.1 million) DALYs in 2019. The age-standardized incidence rate, death rate and DALY rate were 15.6 (14.1–17.2), 11.9 (10.8–12.8), and 268.4 (245.5–290.6) per 100,000 person-years, respectively. Between 1990 and 2019, the global age-standardized incidence rate, death rate, and DALY rate decreased by − 30.5% (− 36.7 to − 22.9), − 41.9% (− 47.2 to − 36.3), and − 45.6% (− 50.8 to − 39.8), respectively. In 2019, most of the global numbers of incidence, death and DALYs were higher among males than females. A considerable burden of stomach cancer was attributable to smoking and a high-sodium diet. Although the global age-standardized incidence and death rates have decreased, continued growth in absolute numbers in some regions, especially in East Asia, poses a major global public health challenge. To address this, public health responses should be tailored to fit each country’s unique situation. Primary and secondary prevention strategies with increased effectiveness are required to reduce the incidence and mortality of stomach cancer, particularly in populations with a high disease burden.

From 1990 to 2019, in all GBD regions, the age-standardized incidence, death and DALY rates for stomach cancer decreased (Fig. 3 Age and sex patterns. In 2019, most of the incidence, death and DALY numbers globally were higher in males than females in all age groups except for the incidence in people older than 90 years, and the death and DALY numbers for those 15-19 years, 20-24 years, 25-29 years, 90-94 years, and 95 plus years. In 2019, most of  www.nature.com/scientificreports/ the global age-standardized incidence, death and DALY rates were higher in males than females, except for the death and DALY rates in those 15-19 years, 20-24 years, and 25-29 years (Fig. 4). The numbers of global incident cases, deaths and DALYs followed a normal distribution and was similar between females and males but peaked at 65-69 years for incident cases and DALYs and peaked at 70-74 years for deaths.
In females, the global age-standardized rates of incidence, mortality, and DALYs increased linearly with age. In males, the global age-standardized rates of incidence, deaths and DALYs increased nonlinearly, peaking at 85-89 years with increasing age. Figure 5 presents the age-standardized DALY rate trends across SDI by region from 1990 to 2019. The patterns are nonlinear, peaking at an SDI value of approximately 0.72, and then decreasing as the SDI values further increase. Most of the regions showed a decreasing trend in the age-standardized DALY rate in this study period, including high-income Asia Pacific, which had the largest decreases. The observed age-standardized DALY rate for East Asia initially decreased and then increased, after which it decreased again as the SDI value further increased.

Burden of stomach cancer by sociodemographic index (SDI).
At the national level, the expected patterns of the age-standardized DALY rates were nonlinear in nature, peaking at an SDI value of approximately 0.6 (Fig. 6). The age-standardized DALY rates of stomach cancer observed in some countries, such as Mongolia, Bolivia, and Afghanistan, were significantly higher than the expected levels, whereas in others, such as Maldives, Switzerland and Saudi Arabia, these rates were lower than the expected levels based on the SDI. Figure S31 shows that the age-standardized incidence rate was highest in high-middle SDI countries/territories (18.8, 95% UI 16.6-21.0) and lowest in low-SDI countries/territories (8.4, 95% UI 7.6-9.3) in 2019. The age-standardized death rates were highest in middle-SDI countries/territories (14.6, 95% UI 13.0-16.3) and lowest in high-SDI countries/territories (7.2, 95% UI 6.5-7.6) in 2019. The DALY ASRs were highest in middle-SDI countries/territories (323.4, 95% UI 285.2-363.0) and lowest in high-SDI countries/territories (145.3, 95% UI 136.6-151.7) in 2019.
Attributable risks. At the global level, for both sexes, a substantial proportion of DALYs were attributable to the two risk factors for which GBD estimates were available: 17.1% (95% UI 13.8% to 20.1%) attributable to smoking and 7.8% (95% UI 0.2% to 30.9%) to a high-sodium diet.
The impact of these risk factors varied among regions. For example, the impact of smoking was highest in Central Europe (21.8%, 95% UI 17.7% to 25.7%) and lowest in western sub-Saharan Africa (5.2%, 95% UI 3.4% to 7.0%) (Fig. 7A). The impact of a high-sodium was highest in East Asia (8.8%, 95% UI 0.2% to 32.8%) and lowest in the Middle East and North Africa (3.5%, 95% UI 0.4% to 19.5%) (Fig. 7B). www.nature.com/scientificreports/ The global patterns of attributable risk differed by age group. The global percentages of attributable DALYs were highest in the 65-69 year age group for smoking and the 50-54 year age group for a high-sodium diet, and they were the lowest in the 30-34 year age group for smoking and in the 95 and over group for a high-sodium diet (Fig. 7C,D).

Discussion
To the best of our knowledge, this GBD-based study is the most recent examination of the global trends and patterns of stomach cancer-related incidence, mortality, DALYs and relevant risk factors. The total number of incident cases, deaths and DALYs increased from 1990 to 2019. However, the age-standardized rates of incidence, mortality and DALYs decreased during the study period. This may have been due to changes in the population age structure and improvements in medical conditions and the implementation of public health care systems 9 . Population growth in many regions, especially in East Asia, resulted in the continuous growth in the absolute number of stomach cancer cases and deaths.
The most recent GLOBOCAN 2020 study estimated that there were 1.1 million incident cases of stomach cancer 2 , which is close to our 2019 estimate (1.3 million, 95% UI 1.2-1.4). Similar to the GLOBOCAN report 2 , the highest age-standardized incidence rates were found in East Asia, high-income Asia Pacific and Andean Latin America in 2019. This finding can be explained in part by differences in the distribution of risk factors associated with gastric cancer 10 . Helicobacter pylori has been categorized by the World Health Organization as a class I human carcinogen and is the most important etiologic agent for stomach cancer, with almost 90% of new cases of noncardia stomach cancer attributed to this bacterium 11,12 . Regions with a high incidence of stomach cancer are prone to high H. pylori seroprevalence rates. A high prevalence of H. pylori infection has been observed in regions of East Asia, high-income Asia Pacific and Andean Latin America 13 . Furthermore, it was estimated that 33% to 50% of all stomach cancer cases were attributable to dietary (high-salt diet with few vegetables) and lifestyle factors (alcohol and coffee consumption and smoking), which are more common in these regions 10,14,15 . Similarly, the GLOBOCAN 2020 study estimated 0.8 million deaths of stomach cancer 2 , which are also close to our 2019 estimates of 1.0 million (95% UI 0.9-1.0). In both these two studies, age-standardized death rates were highest in East Asia, Andean Latin America and Central Asia.
We also analyzed heterogeneous trends in the national age-standardized incidence, mortality, and DALY rates from 1990 to 2019. Mongolia, Bolivia and China had the highest age-standardized incidence rates of stomach cancer in 2019, which was different from the GLOBOCAN 2020 study that found Mongolia, Japan and the Republic of Korea to have the highest age-standardized incidence rates 2 . Similarly, in the GBD 2019 study, the highest age-standardized death rates were found in Mongolia, Bolivia and Afghanistan, whereas in the GLOBCAN 2020 study, the highest rates were found in Mongolia, Tajikistan and Bhutan 2 . The differences in country-specific estimations can be attributed to the data sources and estimation methods used in the two studies 16 . Notably, www.nature.com/scientificreports/ both studies found that Mongolia had the highest age-standardized incidence and age-standardized mortality rate of stomach cancer in the world. This study found higher morbidity and mortality in less developed countries, as indicated by the SDI. East Asia had the highest absolute incidence, death, DALY numbers and rates in 2019, with China contributing more than 90% of the cases. Despite the lower economic cost compared with other countries, China still has the heaviest stomach cancer burden 5 . China has the largest population of all countries, and it is undergoing population aging 17 . Therefore, China is the country with the highest stomach cancer incidence, deaths and DALYs and has higher rates of these indices than the average level worldwide. It is expected that the increasing trend in the number of deaths will continue 18 . However, morbidity will steadily decrease in the future with the improvement of medical treatments and public health strategies.
As expected, the global incidence, mortality and DALYs of stomach cancer were higher in males than in females. The incidences of several types of cancer, including stomach cancer, liver cancer and colon cancer, are far higher in males than in females [19][20][21] . It is speculated that lifestyle differences related to diet and smoking lead to these differences. However, there is growing evidence that the underlying biological sex differences are the basis of these differences. Alexander Sheh demonstrated that 17β-estradiol and tamoxifen can prevent H. pylori infection-associated stomach cancer through the leukocyte recruitment pathway 22 . Many studies have supported a central role of estrogen receptors in stomach cancer [23][24][25] . An improved understanding of estrogen in relation to stomach cancer might provide a novel pathophysiology mechanism and therapeutic target for stomach cancer.
There are multiple risk factors involved in the initiation and progression of stomach cancer. However, the risk burden was primarily attributable to smoking and a high-sodium diet. Several epidemiologic studies have supported the hypothesis that smoking increases the risk of incidence and death of stomach cancer 26,27 . A global burden of disease study reported that since 1990, the age-standardized prevalence of daily smoking was 25% for males and 5.4% for females 28 . Although some countries have implemented smoking restrictions to improve public health and mitigate the disease burden, smoking is still the leading risk factor for stomach cancer and other diseases 29 . Therefore, more effective and comprehensive policies should be applied to further reduce the prevenance of smoking. A high-sodium diet is another important dietary risk factor for stomach cancer, and the risk increases with the sodium consumption level 30,31 . Excess dietary sodium intake is a hazard worldwide and can be severely harmful to human health. In 2010, the average global sodium intake was 3.95 g per day, and regional daily intakes ranged from 2.18 to 5.51 g per day 32 . As the consumption of fresh products and lower salt food increases, stomach cancer mortality decreases 33,34 . The mechanism by which a high-sodium diet induces stomach cancer is associated with direct damage of the gastric mucosa, gastric pit epithelium proliferation, and H. pylori colonization 35 . Sodium restriction is another effective target to reduce the incidence and mortality rates of stomach cancer.
Although H. pylori infection is the strongest risk factor for stomach and treatment options are available, infection was not estimated in this study because the data were unavailable. However, with the improvement of socioeconomic status, the wide application of antibiotics, and the standardization of treatment, the rate of H. pylori infection globally is gradually decreasing, which greatly reduces the burden of stomach cancer 36 . The prevalence of H. pylori infection is still high worldwide, especially in developing countries, which may correlate with living conditions. A meta-analysis of 62 countries showed that approximately 4.4 billion individuals had an H. pylori infection in 2015 37 . H. pylori infection contributes to approximately 89% of stomach cancers. Several studies have reported treating this infection results in a reduction in stomach cancer incidence 38,39 . The research and development of effective medications and enhancing the socioeconomic status of people would help to reduce H. pylori infection rates, which is crucial for successfully reducing the burden of stomach cancer.
A major limitation to the study was our inability to distinguish cardia and noncardia forms of stomach cancer. The descriptive epidemiology and risk factor characteristics of cardia and noncardia stomach cancers differ 40 . Cardia cancer is more common in developed countries, in Caucasian populations, and in people with high socioeconomic status, while noncardia cancer is more common in developing countries, in Black populations, and in people with lower socioeconomic status 41 . H. pylori infection, smoking tobacco, and dietary factors can all increase the occurrence and development of noncardia cancer, while the main risk factors for cardia cancer include gastroesophageal reflux disease, obesity and, possibly, smoking tobacco 15 . In recent decades, unlike the decreasing incidence trends of noncardia cancer, cardia cancer rates have remained stable or have increased around the world 42 . However, changes in the global and regional trends and the burden of cardia versus noncardia tumors are difficult to investigate because the definition of gastric cardia has evolved over time. Furthermore, cardia cancers and esophageal adenocarcinomas are difficult to distinguish because tumors often overgrow the gastroesophageal junction 43 . There were several other limitations to our study. The accuracy of our results highly depended on the quantity and quality of the GBD data that was acquired, but this could be partially compensated for by applying statistical methods. Nevertheless, in regions with scarce data, especially underdeveloped regions, the estimates had to rely on predictive covariates or data from a single country, which is less representative. High-quality studies that are well-matched in location and population should be performed in future rounds of the GBD study. In addition, the influence of race was not taken into account in the GBD datasets; however, risk factors associated with race could be a consideration for stomach cancer. In addition, as discussed above, the burden of stomach cancer cannot be solely attributed to H. pylori infection, and the lack of data on other risk factors (e.g., excess body weight, medication use, and Epstein-Barr virus infection) limited our risk factor analysis.
Stomach cancer will continue to be a major public health burden because the majority of cases are diagnosed at an advanced stage when treatment options are limited and prognosis is poor. Thus, early screening for stomach cancer is urgently needed. Primary preventive strategies aimed at reducing risk factors and promoting protective factors will lead to a decrease in the incidence of stomach cancer. H. pylori eradication is recommended as the best primary prevention strategy 44 . The decrease in H. pylori infections in Japan is believed to have contributed to a decline in stomach cancer cases 45  www.nature.com/scientificreports/ primary prevention of stomach cancer is still under debate 46 . Neoplastic transformation of the gastric mucosa is a multistep process, and early diagnosis and appropriate management of preneoplastic conditions can reduce stomach cancer-related mortality. Therefore, several screening strategies have been proposed to detect neoplastic lesions at the early stage. At present, white light endoscopy with mapping biopsy remains the gold standard for stomach cancer diagnosis, and it is used for stomach cancer screening in high-risk areas (e.g., Japan, Korea, and Venezuela) due to its high detection rate 47 . By combining magnifying endoscopy and image-enhanced endoscopy, irregularities in the surface structures can be evaluated and highlighted, leading to improvements in the diagnostic accuracy of early-stage stomach cancer 48 . As a noninvasive test, the combination of pepsinogen, gastrin and anti-H. pylori antibody serological assays have been used for screening individuals and populations with a higher risk for gastric preneoplastic lesions 49,50 . Population screening is recommended in areas with a high incidence of stomach cancer, while individual screening is recommended for high-risk people who live in areas with a low incidence 51 . In Japan and South Korea, national population screening programs have been implemented and have been shown to be effective in reducing stomach cancer mortality 52,53 . A recent systematic review and meta-analysis confirmed the validity of endoscopic screening in Asian countries, reporting a 40% RR reduction in stomach cancer mortality 54 . To reduce stomach cancer incidence and mortality, primary and secondary prevention strategies with increased effectiveness are needed. This study provides an updated estimate on the global stomach cancer burden and can be useful for defining new strategies for the early detection, treatment, and management of stomach cancer. Improved economic conditions that decrease the H. pylori infection rate and targeting risk factors, such as smoking and sodium intake, are expected to decrease stomach cancer incidence and mortality.

Methods
Study data. The GBD 2019 study, conducted by the Institute of Health Metrics and Evaluation (IHME), is the largest and most comprehensive effort to epidemiologically assess disease burdens and trends globally. GBD 2019 estimated the burden of 369 diseases and injuries; 286 causes of death; and 87 behavioral, environmental, occupational, and metabolic risk factors by region, sex, country, and age in 204 countries and territories, 7 super regions, and 21 regions from 1990 to 2019. In the current study, data on the disease burden of stomach cancer were obtained through an online query tool from the Institute for IHME website (http:// ghdx. healt hdata. org/). The general methodology of GBD 2019 has been explained in previous publications [55][56][57][58] . Detailed information on the estimation process of fatal and non-fatal outcomes in stomach cancer is described in the Supplementary methods.
The institutional review board of the Third Xiangya Hospital of Central South University determined that the study did not need approval because all data used in this study were publicly available. This study followed the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) reporting guidelines for cross-sectional studies 59 .
Case definition. Stomach cancers are diagnosed by endoscopy, imaging, and biopsy conducted in patients with relevant clinical signs and symptoms.

Risk factors.
The GBD 2019 used the comparative risk assessment framework used in the GBD since 2002 to quantify associations between disease and risk factors. Risk factors were divided into 3 categories: behavioral, environmental/occupational, and metabolic. Among the 87 risk factors assessed by GBD 2019, two major risk factors for stomach cancer were confirmed: smoking and a high-sodium diet. www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.